Fimasartan (FMS), an angiotensin II receptor antagonist, is metabolized to FMS S-oxide, FMS N-glucuronide, oxidative desulfurized FMS (BR-A-557), and hydroxy-n-butyl FMSs. The purpose of this study was to characterize enzymes involved in NADPH-dependent FMS metabolism using recombinant enzymes such as cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO), as well as selective chemical inhibitors. The results showed that CYP, but not FMO, plays a major role in FMS metabolism. CYP2C9, CYP3A4, and CYP3A5 were involved in the formation of FMS S-oxide, which was further metabolized to BR-A-557 by CYP3A4/5. CYP2C9 played an exclusive role in n-butyl hydroxylation. The specificity constant (kcat/Km) values for S-oxidation by CYP2C9, CYP3A4, and CYP3A5 were 0.21, 0.34, and 0.19 μM-1∙min-1, respectively. The kcat/Km values of hydroxylation at the 1-, 2-/3-, and 4-n-butyl group in CYP2C9 were 0.0076, 0.041, and 0.035 μM-1∙min-1, respectively. The kcat and Km values provide information for the prediction of FMS metabolism in vivo. In addition, simultaneous determination of the FMS metabolites may be used to evaluate CYP2C9 and CYP3A4/5 activity.

血管紧张素II受体拮抗剂Fimasartan（FMS）被代谢为FMS S-氧化物，FMS N-葡糖醛酸，氧化脱硫FMS（BR-A-557）和羟基正丁基FMS。这项研究的目的是使用重组酶（例如细胞色素P450（CYP）和含黄素的单加氧酶（FMO））以及选择性化学抑制剂来表征与NADPH依赖的FMS代谢有关的酶。结果表明，CYP而非FMO在FMS代谢中起主要作用。CYP2C9，CYP3A4和CYP3A5参与了FMS S-氧化物的形成，并被CYP3A4 / 5代谢为BR-A-557。CYP2C9在正丁基羟基化中起独家作用。CYP2C9，CYP3A4和CYP3A5对S氧化的特异性常数（kcat / Km）分别为0.21、0.34和0.19μM-1∙min-1。CYP2C9中1-，2- / 3-和4-n-丁基羟基化的kcat / Km值分别为0.0076、0.041和0.035μM-1∙min-1。kcat和Km值为体内FMS代谢的预测提供信息。此外，同时测定FMS代谢物可用于评估CYP2C9和CYP3A4 / 5活性。